Liver & intrahepatic bile ducts

Other malignancies

Intrahepatic cholangiocarcinoma (small and large duct types)


Editorial Board Member: Monika Vyas, M.D.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Jennifer Vazzano, D.O., M.S.
Wei Chen, M.D., Ph.D.

Topic Completed: 23 August 2021

Minor changes: 7 September 2021

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PubMed Search: Cholangiocarcinoma [title] liver "intrahepatic bile duct" pathology

Jennifer Vazzano, D.O., M.S.
Wei Chen, M.D., Ph.D.
Page views in 2020: 36,355
Page views in 2021 to date: 35,174
Cite this page: Vazzano J, Chen W. Intrahepatic cholangiocarcinoma (small and large duct types). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/livertumorcholangiocarcinoma.html. Accessed October 15th, 2021.
Definition / general
  • Intrahepatic cholangiocarcinoma (iCCA) is a malignant intrahepatic epithelial neoplasm with biliary differentiation, arising in the liver periphery / proximal to the left and right hepatic ducts (WHO 2019)
  • iCCA classification systems (Surg Pathol Clin 2018;11:403, Nat Rev Gastroenterol Hepatol 2020;17:557):
    • Histologic features
    • Macroscopic growth pattern
      • Mass forming
      • Periductal infiltrating
      • Intraductal
      • Mixed growth patterns
    • Cell of origin
      • Stem cells residing in the canals of Hering
      • Stem cells within peribiliary glands
Essential features
  • Nonencapsulated, white-tan and firm intrahepatic mass
  • Glandular malignancy with various degrees of atypia and differentiation, infiltrating a dense fibrous stroma
  • Exclusion of metastatic adenocarcinoma by review of the patient's clinical history and application of an appropriate immunohistochemistry panel
  • Large duct type iCCA: often hilar masses, obstructive cholestasis; share risk factors with extrahepatic bile duct adenocarcinomas (primary sclerosing cholangitis [PSC], liver fluke infection)
  • Small duct type iCCA: peripheral, larger liver masses; shares risk factors with hepatocellular carcinomas (viral hepatitis, nonbiliary cirrhosis)
Terminology
  • Also known as peripheral cholangiocarcinoma and intrahepatic bile duct carcinoma
ICD coding
  • ICD-10: C22.1 - intrahepatic bile duct carcinoma
Epidemiology
  • In the United States, the average annual incidence is 1.6 per 100,000/year (Cancer Control 2017;24:1073274817729245)
  • 15% of primary liver malignancies worldwide
  • Second most common malignancy arising from the liver
  • 3% of all cases of gastrointestinal cancer
  • ~10% of all bile duct carcinomas
  • More common in East Asia, due to endemic liver fluke infection
  • Most patients are aged between 55 and 75 years (Cancer Lett 2016;379:198)
  • M > F (Cancer Lett 2016;379:198)
Pathophysiology
  • Chronic inflammation of the intrahepatic bile ducts with sustained IL6-STAT3 signaling (Nat Rev Gastroenterol Hepatol 2020;17:557)
  • IDH, EPHA2 and BAP1 mutations and FGFR2 fusions in iCCA; in contrast to PRKACA and PRKACB fusions, ELF3 and ARID1B mutations in extrahepatic tumors (Nat Genet 2015;47:1003)
  • TP53 and SMAD4 mutations
  • CpG island hypermethylation are more frequent in liver fluke associated cholangiocarcinoma
Etiology
Diagrams / tables

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Classifications of
cholangiocarcinoma

Clinical features
  • Asymptomatic in early stages (Nat Rev Clin Oncol 2018;15:95)
  • Nonspecific symptoms in late stages, such as abdominal pain, malaise, fever, night sweats and weight loss / cachexia
  • Jaundice / biliary obstruction are uncommon in iCCA, compared with extrahepatic cholangiocarcinoma
Diagnosis
  • Clinicopathologic diagnosis by correlation of radiological, laboratory and surgical pathology findings
  • Broad investigation of hepatic pathology and other malignancies should be conducted
    • Colon cancer risk / screening history
    • Alcohol consumption history
    • Travel history (liver flukes)
    • Viral hepatitis risk and serologies
    • Autoimmune hepatitis serologies
    • Iron studies (hemochromatosis), copper studies (Wilson disease)
    • BMI (NASH)
    • Exposure to hepatotoxins (thorotrast, aflatoxin)
  • Labs
    • CA 19-9, CEA, AFP
    • In patients with PSC with or without ulcerative colitis, development of CCA can be predicted with CA 19-9 (a proposed cutoff level of 130 U/mL carries a sensitivity and specificity of 78.6% and 98.5% respectively
  • Reference: Surg Oncol Clin N Am 2019;28:587, Surg Pathol Clin 2018;11:403
Laboratory
Radiology description
  • Usually single, large, homogeneous mass with irregular margins on CT scan
  • No pathognomonic CT / MRI features: may show progressive delayed enhancement, peripheral rim enhancement, subcapsular retraction
  • Reference: Radiology 2018;288:7
Radiology images

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CT scan

Ultrasound

MRI

Prognostic factors
  • Serum CEA, CA 19-9, tumor diameter and number, lymph node metastasis, vascular invasion and direct invasion and local extrahepatic metastasis are important prognostic factors (J Clin Oncol 2013;31:1188)
  • Periductal infiltration and AJCC 8th edition pT stage (Am J Surg Pathol 2018;42:1334)
Case reports
Treatment
  • Surgical resection of the tumor is the potential curative therapy
  • Frequently inoperable, often recur after surgery
  • First line treatment for locally advanced or metastatic disease is gemcitabine / cisplatin
  • Molecular testing recommended by National Comprehensive Cancer Network (NCCN) for unresectable and metastatic tumors (> 50% of NGS tested subjects have potentially actionable mutations)
  • Ongoing clinical trials of targeted therapy: immune checkpoint inhibitors (anti-PD1, anti-PDL1, anti-CTLA4 antibodies), IDH1 inhibitors, AKT / PI3K / mTOR inhibitors, FGFR inhibitors and anti-EGFR and MEK inhibitors
  • Reference: Surg Oncol Clin N Am 2019;28:587
Gross description
  • Usually large, nonencapsulated, well demarcated, firm (due to desmoplastic reaction), white-tan to gray and nodular intrahepatic mass
  • More frequent in the right lobe of the liver
  • Satellite nodules are present in 30%
  • Calcification is common
  • Noncirrhotic background liver in most cases
  • Grossly classified into 3 growth patterns (J Gastroenterol 2013;48:647):
    1. Mass forming: hepatic parenchymal solid mass
    2. Periductal infiltrating: infiltrates along the portal tracts, causing bile duct strictures
    3. Intraductal growth: papillary or polypoid growth inside a dilated bile duct
Gross images

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Mass forming cholangiocarcinomas

Periductal infiltrating cholangiocarcinoma

Frozen section description
  • Margin status may be assessed via frozen section
  • Invasive foci of cholangiocarcinoma are infiltrating glands found as direct stromal invasion, vessel invasion or perineural invasion
Frozen section images

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Invasive
cholangiocarcinoma

Microscopic (histologic) description
  • iCCA consists of infiltrating well formed or cribriform glands in an abundant fibrous stroma (Liver Int 2019;39:7, Surg Pathol Clin 2018;11:403)
  • Malignant glands are lined by cells with varying degrees of atypia and pleomorphism (Liver Int 2019;39:7)
  • Usually well differentiated adenocarcinoma with mild atypia, intracytoplasmic lumina and intraluminal cellular debris; however, focal atypia with marked pleomorphism can also be present (Liver Int 2019;39:7)
  • Commonly infiltrates between hepatic parenchymal cords at the periphery of the tumor
  • Multicentricity and perineural invasion are common
  • Histologic variants include mucinous, signet ring cell, clear cell, lymphoepithelioma-like, thyroid follicular-like, adenosquamous and sarcomatoid
  • Small duct type iCCA (Liver Int 2019;39:7)
    • Peripheral hepatic parenchyma
    • Mass forming
    • Cuboidal cells forming small tubular or anastomosing glands
    • Variable lymphovascular / perineural invasion
    • CD56, N-cadherin, CRP positive
    • Subtypes include cholangiolocarcinoma, iCCA with ductal plate malformation-like pattern
  • Large duct type iCCA (Liver Int 2019;39:7)
    • Proximal to liver hilum
    • Periductal infiltrating or mass forming
    • Tall columnar cells that form large glands within open lumina; usually contain mucin
    • BilIN, IPNB, ITPN are precursors
    • Positive lymphovascular / perineural invasion
    • MUC5AC, MUC6, S100P and TFF1 positive
Microscopic (histologic) images

Contributed by Wei Chen, M.D., Ph.D. and Omid Savari, M.D.

Large duct type iCCA

Small duct type iCCA

Anastomosing glands

Ductal plate malformation pattern

With necrosis


With sclerotic stroma

Irregular nuclear features

Irregular nuclear features

Infiltrating hepatic parenchyma

Poorly differentiated

Cytology description
  • Isolated clusters and sheets of cuboidal or columnar cells with various degrees of nuclear enlargement and pleomorphism
  • Wide range of glandular differentiation on cell block; > 10 proliferating ductules on FNA is helpful to differentiate cholangiocarcinoma from metastatic adenocarcinomas (Diagn Cytopathol 2000;22:359)
Cytology images

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Cholangiocarcinoma
on FNA

Positive stains
Negative stains
Molecular / cytogenetics description
  • Mutations in KRAS (22%), BRAF (7%), EGFR (2%), IDH1 / IDH2 (14%), MET, activation of mTOR, overexpression of cyclin D1, overexpression of p21, inactivating mutations of DPC4 / SMAD4 (13 - 15%) and TP53 (15%) (BMC Cancer 2019;19:185)
  • Chromosomal gains of 1q, 5p, 7p, 8q, 17q and 20q and losses of 1p, 4q, 8p, 9p, 17p and 18q (BMC Cancer 2019;19:185)
Sample pathology report
  • Right lobe of liver, partial hepatectomy:
    • Moderately differentiated adenocarcinoma, 6.5 cm, consistent with intrahepatic cholangiocarcinoma, small duct type
    • Resection margins are negative for carcinoma
    • Lymphovascular invasion present
    • Metastatic adenocarcinoma involving 1 of 3 lymph nodes
    • Pathologic TNM stage (AJCC 8th edition): pT2N1
    • Background liver with mild steatosis and steatohepatitis; no advanced fibrosis
Differential diagnosis
Board review style question #1

Which of the following is a feature of small duct type Intrahepatic cholangiocarcinoma (iCCA)?

  1. Arises from peribiliary glands
  2. Cuboidal cells forming small tubular or anastomosing glands
  3. Positive for S100P and TFF1 immunostains
  4. Tall columnar cell lined glands with luminal mucin production
Board review style answer #1
B. Cuboidal cells forming small tubular or anastomosing glands

Comment Here

Reference: Intrahepatic cholangiocarcinoma (small and large duct types)
Board review style question #2
Which of the following regarding intrahepatic cholangiocarcinoma (iCCA) risk factors is true?

  1. Alcoholic steatohepatitis / nonalcoholic steatohepatitis are risk factors for large duct type iCCA
  2. Biliary type cirrhosis is an independent risk factor for small duct type iCCA
  3. Chronic inflammation of the biliary epithelium is a common risk factor
  4. Primary sclerosing cholangitis is a risk factor for small duct type iCCA
Board review style answer #2
C. Chronic inflammation of the biliary epithelium is a common risk factor

Comment Here

Reference: Intrahepatic cholangiocarcinoma (small and large duct types)
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